Research in this program is focused on the basic mechanisms by which the host mobilizes and modulates cellular inflammatory reactions in defense against foreign antigens and infectious agents. In a multi-disciplinary approach, mechanisms of integrin adhesion, chemotaxis, signaling, mediator synthesis and apoptosis are explored in vitro and extended into experimental animal models (bacterial induced rodent arthritis; knockout and transgenic mice) for in vivo analysis. In addition, human conditions of chronic inflammatory disease in response to foreign implants, infectious pathogens, or of unknown etiology are explored at the cellular, molecular and biochemical levels. Understanding the mechanisms which control normal immune cell recruitment, activation and/or deletion and the switch to pathogenesis underlies the development of strategies for modulating chronic pathogenic inflammatory diseases. In an experimental model of arthritis, we have characterized the immunopathology through phenotypic, functional and morphologic parameters, in addition to DNA microarrays and ribonuclease protection assays, to identify targets for therapeutic intervention including leukocyte adhesion, signal transduction, cytokines, proteases, and nitric oxide. New insights into the regulation of immune function through TGF-beta, including TGF-beta-mediated apoptotic pathways in T lymphocytes, raise the prospect of novel approaches to controlling immunological tolerance. Both thymic and peripheral T cell apoptosis was found to be increased in mice null for TGF-beta compared to wildtype littermates. Strikingly, TGF-beta was localized to mitochondria in wildtype cells, and the absence of TGF-beta in null mice resulted in disruption of lymphocyte mitochondrial membrane potential and apoptosis, supporting a regulatory role for this cytokine in T cell selection and tolerance. In additional studies, synovial gene transfer of a tumor necrosis factor (TNF) antagonist was found to suppress bacterial cell wall-induced arthritis as effectively as systemic delivery, which may serve to abrogate potential side effects associated with systemic biodistribution of TNF inhibitors.